Baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and is chemically known as 4-amino-3-(4-chlorophenyl)-butanoic acid. It is a GABA-agonist that acts through presynaptic and postsynaptic pathways. The primary site of action is the spinal cord where baclofen reduces the release of excitatory neurotransmitters. It is used to help relax certain muscles in the body. Baclofen relieves the spasms, cramping, and tightness of muscles caused by medical problems such as multiple sclerosis, cerebral palsy, or certain injuries or diseases of the spine. It is approved worldwide for the alleviation of signs and symptoms of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus and muscular rigidity.
There is a wide inter-subject variation in the absorption and elimination of baclofen, but on an average it is rapidly and extensively absorbed after oral administration. Plasma elimination half-life of baclofen is approximately 3.5 hours (range 2 to 6 hours). Baclofen is excreted mainly by the kidneys in unchanged form although 15% is metabolized in the liver. Conventional baclofen therapy involves administration of immediate release tablets for example 10 mg or 20 mg immediate release tablets three times a day. The dose ranges from 30 mg to 100 mg/day in divided doses. Baclofen is also available in the USA for chronic use as an injection to be administered by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture), and as implantable pumps approved by the Food and Drug Administration specifically for the administration of baclofen injection into the intrathecal space.
The term “immediate release baclofen tablets” as used herein means baclofen tablets that disintegrate in gastric fluids and release the baclofen into gastric fluids shortly thereafter. Frequent administration of immediate release baclofen tablets leads to fluctuations in plasma concentration producing peaks and troughs with peaks being associated with side effects, such as drowsiness (sedation), dizziness and muscle weakness and troughs causing inadequate control of muscle spasm. Side effects, like drowsiness and muscle weakness, are considered as major deterrents to the prescribers for up titration of the dosage for optimization of therapy. It is a matter of general concern, with conventional baclofen therapy, that the medication has to be administered frequently. Medication noncompliance among patients with medical illnesses has been reported to range from 15% to 85%. Although many factors are associated with medication noncompliance, it is thought that physicians can help promote compliance by prescribing medications that require a minimal number of doses. A once-a-day or twice-a-day (b.i.d.) dosage formulation with the same therapeutic effectiveness as the conventional baclofen therapy would vastly improve patients' compliance with treatment. These will also increase the outcome of therapy, as more number of patients will adhere to treatment plan.
However, prior art has taught that controlled, sustained or modified release systems that delay baclofen release beyond 8 hours may not be suitable. Merino et al, Proc. Eur. Congr. Biopharm. Pharmacokinet., 3rd (1987), 2, 564-73, describes studies of intestinal absorption of baclofen in the rat small intestine. This reference concludes that administration of sustained-release forms of the drug or the use of increased doses of baclofen to obtain better therapeutic responses may not be suitable for clinical practice in humans.
Merino et al, Biopharmaceutics and Drug Disposition (1989), 10(3), 279-97, also describes studies of intestinal absorption of baclofen in the rat small intestine. The authors have recommended the administration of usual doses of baclofen at shorter intervals when higher plasma levels at steady-state are needed, and that more than 8-hour sustained-release preparations of baclofen should be avoided.
Baclofen crosses the blood brain barrier with concentrations in the cerebrospinal fluid (CSF) corresponding to about 12% of those in the plasma. The elimination half-life of baclofen from the CSF is about 4-5 hours. The amount of drug retained in the CSF is therefore responsible for providing the therapeutic effect of baclofen. The lowest concentration in plasma at which a significant reduction in spasticity was observed was 90 ng/ml (see “Plasma and cerebrospinal fluid levels of baclofen (Lioresal®) at optimal therapeutic response in spastic paresis”; Evert Knutsson, Ulf Lindblom and Anders Martensson, J. Neurological Sciences, 1974, 23: 473-484) Conventional release tablets, that are administered two or three times a day, provide peaks and valleys in the plasma concentration, and therefore, in the CSF concentration, which is not desirable. We tried to address this problem in our co-pending PCT application WO 03/011255A1 (the '255 application), which discloses an oral controlled drug delivery system for baclofen, and which is incorporated herein by reference. It exemplifies formulations that provide blood levels such that the system may be suitable for once a day administration. In our continued efforts to develop systems that provide better efficacy in alleviating the signs and symptoms of spasticity, we designed controlled drug delivery systems that provide higher plasma levels of baclofen than the systems of the '255 application (see our co-pending PCT application WO 2005/101983 A1 (the '983 application), which is incorporated herein by reference). Plasma levels higher than those provided by conventional baclofen therapy were achieved using the system of the '255 application, as well as the system of the '983 application, in healthy human volunteers. Thus, both of our systems were expected to provide better therapeutic efficacy as compared to conventional baclofen therapy, however, the increased plasma levels of baclofen were expected to give rise to more side effects associated with baclofen therapy, particularly on multiple dosing. Further, it was not known which of the systems would be preferred for clinical use of baclofen, for alleviating the signs and symptoms of spasticity in patients.
We have found a method for alleviating the signs and symptoms of spasticity by orally administrating once-a-day a controlled drug delivery system, which method surprisingly and unexpectedly provided statistically significant lower level of sedation, even on repeated or multiple dosing, than that associated with conventional baclofen therapy.